Diabetes mellitus is currently classified into Type I or insulin- dependent diabetes mellitus (IDDM) and Type II or noninsulin- dependent diabetes mellitus (NIDDM). In the United States there are approximately 500,000 cases of IDDM and 5,000,000 with NIDDM. Genetic association has been shown for IDDM (the HLA locus on Chromosome 6 and the hypervariable region near the insulin gene on chromosome 11) but except for a rare patient with a mutant insulin gene, there have been no similar genetic associations found for NIDDM despite its very strong familial nature. Recently it has become well-established that two defects coexist in most patients with NIDDM, impaired glucose-induced insulin release and insulin resistance. In the proposed studies it is planned to take advantage of the fact that: analysis of restriction fragment length polymorphisms (RFLPs) have been demonstrated to be powerful in dissecting the molecular basis for a number of diseases; a well characterized patient population is available; and we have probes to examine a number of genes that are candidates to be abnormal in noninsulin- dependent diabetes mellitus. Blood samples will be obtained from patients with NIDDM as well as nondiabetics who are characterized on the basis of their beta cell secretory capacity and their insulin sensitivity. DNA isolated from leukocytes will be cleaved with a variety of restriction endonucleases and probed with DNA growth factor-II (IGF-II), the insulin receptor, the glucose transport protein, and other candidate genes as they become available. The data will be analyzed for positive correlations between the RFLPs and indices of beta cell function and insulin sensitivity. In cases having positive correlations familial studies will be performed to confirm the association through linkage disequilibrium. These studies therefore show promise for detecting potential primary defects in noninsulin-dependent diabetes mellitus that could be useful in predicting susceptibility and more importantly for determining future studies aimed at elucidating the primary defects.